Leptin is a hormone primarily involved in the regulation of basal metabolism that also has an important role in immune responses. Leptin promotes inflammation and can accelerate onset and progression of several autoimmune diseases including systemic lupus erythematosus (SLE). Because of that, we will test whether leptin-based intervention may be beneficial for the course of SLE in a mouse model of SLE, the (NZB x NZW)F1 (NZB/W F1) mouse. Since we hypothesize that leptin affects the phenotype and function of some immune-cell subsets and intereferes/promotes the release of soluble mediators in order to exert its propathogenic effects in SLE, we will dissect several cellular and molecular events induced by leptin in NZB/W F1 mice. We will study the effects of leptin on autoreactive T cells and will characterize some intracellular signaling events induced by leptin. We will then test different approaches of leptin-based intervention in these mice to ultimately set the stage for translational studies to humans. By defining some crucial aspects related to the physiopathology of leptin in the development of systemic autoimmunity in NZB/W F1 mice, these studies will explore new strategies of therapeutic intervention in lupus mice for future translational research in humans aimed at improving management of this incurable disease.